2-(4-Substituted alkyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one derivatives

ABSTRACT

2-(4-Substituted alkyl-1-piperazinyl)-2,4,6-cycloheptatrien-1-one derivatives, therapeutically acceptable acid addition salts thereof, processes for their preparation, methods of using the derivatives and pharmaceutical compositions of the derivatives are disclosed. The derivatives exhibit dopamine-receptor stimulating activity in a mammal and are useful for treating hyperprolactinemia, galactorrhea, amenorrhea, impotence, Parkinsonism, diabetes, acromegaly, hypertension and other central nervous system disorders.

BACKGROUND OF THE INVENTION

This invention relates to novel2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one derivatives, totherapeutically acceptable acid addition salts thereof, to a process fortheir preparation, to methods of using the derivatives and topharmaceutical compositions of the derivatives. These derivativesexhibit dopamine-receptor stimulating activity in a mammal. Thus, theycan be useful for treating hyperprolactinemia, galactorrhea, amenorrhea,impotence, Parkinsonism, diabetes, acromegaly, hypertension and othercentral nervous system disorders which respond to dopamine-receptorstimulation.

The following references were obtained from a literature search for2-substituted tropones: E. Sianesi et al., J. Med. Chem., 10, 1144(1967); G. Biggi et al., J. Amer. Chem. Soc., 94, 4700 (1972); T. Todaet al., Chem. Abstr., 76, 72185f (1972) for Bull. Chem. Soc. Jap., 45,226 (1972); G. Biggi et al., J. Amer. Chem. Soc., 95, 7101 (1973); C. A.Veracini et al., J. Chem. Soc. Commun., 623 (1974); B. J. Abadir et al.,J. Chem. Soc., 2350 (1952) and T. Nozoe et al., Chem. Abstr., 70, 87244z(1969) for Bull. Chem. Soc. Jap., 41, 2978 (1968). These referencesdisclose compounds which like the compounds of this invention are2,4,6-cycloheptatrien-1-one derivatives. Of these2,4,6-cycloheptatrien-1-one derivatives, the2-piperidinyl-2,4,6-cycloheptatrien-1-one described by G. Biggi et al.,J. Amer. Chem. Soc., 94, 4700 (1972), cited above, can be considered themost closely related to the compounds of this invention. However, thelatter 2-piperidinyl derivative is treated as a chemical curiositywithout any indicated useful pharmacological activity. Furthermore, thecompounds of this invention differ from the compounds of Biggi et al.,by having a 1-piperazinyl group at position 2 of the2,4,6-cycloheptatrien-1-one ring.

SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula I ##STR1## inwhich Alk is a divalent alkyl having one to six carbon atoms; R¹ ishydrogen or lower alkyl having one to three carbon atoms; and R² islower alkoxy, cyano, aminocarbonyl, lower alkoxycarbonyl,cyclo(lower)alkyl, phenyl, phenoxy, hydroxy(lower)alkoxy, 3-indolyl,1-oxo-2,4,6-cycloheptatrien-2-yl-amino, 1H-imidazol-4-yl,1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- or trisubstituted withlower alkyl, halo, lower alkoxy, hydroxy or trifluoromethyl, or phenoxymono-, di- or trisubstituted with lower alkyl, halo, lower alkoxy,acetylamino, hydroxy or trifluoromethyl; or a therapeutically acceptableacid addition salt thereof.

A preferred group of compounds of this invention is represented byformula I in which Alk is a divalent alkyl having one to six carbonatoms; R¹ is hydrogen; and R² is lower alkoxy, cyano, aminocarbonyl,lower alkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- ortrisubstituted with lower alkoxy or hydroxy, or phenoxy mono-, di- ortrisubstituted with lower alkyl, halo or acetylamino; or atherapeutically acceptable acid addition salt thereof.

A more preferred group of compounds of this invention is represented byformula I in which Alk is a divalent alkyl having one to three carbonatoms; R¹ is hydrogen; and R² is lower alkoxy, cyano, aminocarbonyl,lower alkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono- ordisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstitutedwith lower alkyl, halo or acetylamino; or a therapeutically acceptableacid addition salt thereof.

A most preferred group of compounds of this invention is represented byformula I in which Alk is a divalent alkyl having one or two carbonatoms; R¹ is hydrogen; and R² is lower alkoxy, cyano,1-oxo(lower)alkoxy, or phenyl mono- or disubstituted with lower alkoxyor hydroxy; or a therapeutically therapeutically acid addition saltthereof.

A pharmaceutical composition is provided by admixing the compound offormula I, or a therapeutically acceptable acid addition salt thereof,with a pharmaceutically acceptable carrier.

The compounds of this invention are used to stimulate dopamine receptorsin a mammal in need thereof by administering to the mammal an effectivedopamine receptor stimulating amount of a compound of formula I or atherapeutically acceptable acid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein means straight chain alkylradicals containing from one to six carbon atoms and branched chainalkyl radicals containing three or four carbon atoms and includesmethyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl,hexyl and the like, unless stated otherwise. 1-Methylethyl and2-methylpropyl also are known as isopropyl and see-butyl.

The term "lower alkoxy" as used herein means straight chain alkoxyradicals containing from one to six carbon atoms and branched chainalkoxy radicals containing three or four carbon atoms and includesmethoxy, ethoxy, 1-methylethoxy, butoxy, hexoxy and the like.

The term "1-oxo(lower)alkyl" or "lower alkanoyl" as used herein meansstraight chain 1-oxoalkyl radicals containing from two to six carbonatoms and branched chain 1-oxoalkyl radicals containing four to sixcarbon atoms and includes acetyl, 1-oxopropyl, 2-methyl-1-oxopropyl,1-oxohexyl and the like.

The term "1-oxo(lower)alkoxy" as used herein means straight chain1-oxoalkoxy radicals containing from two to six carbon atoms andbranched chain 1-oxoalkoxy radicals containing four to six carbon atomsand includes acetyloxy, 1-oxopropoxy, 1-oxobutoxy,2,2-dimethyl-1-oxopropoxy, 1-oxohexoxy and the like.

The term "halo" as used herein means halogens and includes fluorine.

The term "halo"as used herein means halogens and includes fluorine,chlorine, bromine and iodine, unless stated otherwise.

The term "cyclo(lower)alkyl" as used herein means saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "--Alk--" as used herein means a divalent alkyl radical derivedfrom a straight and branched chain aliphatic hydrocarbons containingfrom one to six carbon atoms by removal of two hydrogen atoms, unlessstated otherwise, and includes, for example ##STR2## and the like.

The term "lower alkanol" as used herein means both straight and branchedchain alkanols containing from one to four carbon atoms and includesmethanol, ethanol, isopropanol, butanol and the like.

The term "organic proton acceptor" as used herein means the organicbases, or amines for instance, triethylamine, pyridine,N-ethyl-morpholine, 1,5-diazabicyclo[4.3.0]non-5-ene and the like.

The term "inorganic proton acceptor" as used herein means the inorganicbases, preferably the alkali metal hydroxides, carbonates andbicarbonates, for example, sodium hydroxide, potassium hydroxide, sodiumcarbonate, sodium bicarbonate, potassium carbonate and the like.

The term "proton acceptor" as used herein means a proton acceptorselected from an organic proton acceptor and inorganic proton acceptor,as defined herein.

The compounds of formula I are capable of forming acid addition saltswith therapeutically acceptable acids. The acid addition salts areprepared by reacting the base form of the appropriate compound offormula I with one or more equivalents, preferably with an excess, ofthe appropriate acid in an organic solvent, for example, diethyl etheror an ethanol-diethyl ether mixture. These salts, when administered to amammal, possess the same pharmacologic activities as the correspondingbases. For many purposes it is preferable to administer the salts ratherthan the base compounds. Examples of suitable acids to form these saltsinclude: the common mineral acids, e.g., hydrohalic, sulfuric orphosphoric acids; the organic acids, e.g., formic, acetic, maleic,malic, citric, or tartaric acid; and acids which are sparingly solublein body fluids and which impact slow-release properties to theirrespective salts, e.g., pamoic acid, tannic acid or carboxymethylcellulose. The addition salts thus obtained are the functionalequivalent of the parent base compound in respect to their therapeuticuse. Hence, these addition salts are included within the scope of thisinvention and are limited only by the requirement that the acidsemployed in forming the salts be therapeutically acceptable.

The discovery in the mid-1960's of two major dopamine (DA) systemsindicated that this neurotransmitter exerted control over a number ofphysiological functions. Against this background an interest arose todevelop DA receptor agonists to study the function of the dopaminergicsystems and to evaluate these agonists as possible therapeutic agents inParkinson's disease and certain neuroendocrine disorders, for example,hyperprolactinemia, galactorrhea, amenorrhea, impotence, hypertensionand other central nervous system disorders.

The DA receptor agonists exert a variety of pharmacological effects,some of the most characteristic being the ones that occur in animals inwhich DA deficiency is brought about to mimic the Parkinsonian syndrome.An important model was developed by U. Ungerstedt, Acta. Physiol.Scand., Suppl. 367, 69-93 (1971) who, by means of unilateral injectionsof 6-hydroxydopamine (6-OHDA) into the DA pathway, could produceselective lesions of the ascending DA pathways on one side of the brain.Ungerstedt (1971) demonstrated in these lesioned rats that DA receptoragonists induced rotational behavior towards the innervated side. Theresponse is due to the development of receptor supersensitivity in thedenervated striatum resulting in a higher degree of DA receptor activityon the denervated--as compared to the innervated--side after treatmentwith DA receptor agonists. Due to this imbalance between the two sides,a rotational behavior is elicited, the direction being always towardsthe less activated side. It is of interest that in the discovery of theDA receptor stimulating properties of bromocriptine, the 6-OHDArotational model was utilized [H. Corrodi et al., J. Pharm. Pharmacol.,25, 409-412 (1973)].

In the test for rotational behavior in rats following the unilateral6-OHDA-induced destruction of one nigrostriatal pathway, the methoddescribed by C. J. Pycock and C. D. Marsden, Europ. J. Pharmacol., 47,167 (1978) was followed. The rats (230-250 g) were anesthetized withsodium pentobarbital (40 mg/kg i.p.) and intracerebral injections weremade using a Stoelting stereo-taxic instrument, (C. H. Stoelting Co.,Chicago, Ill., U.S.A.). Unilateral injections of 6-OHDA hydrobromide (8μl delivered at a rate of 1 μl per min) were made into the ascendingforebrain bundle (MFB) in the lateral hypothalamus according to thecoordinates of the De Groot brain atlas, J. De Groot, Verhandel,Koninkl. Ned. Akad. Wetenschap. Natuurk. 52; 1-40 (1959), (A: +4.6, L:±1.9, V: -2.7). 6-OHDA was made up in ice-cold distilled watercontaining 0.2 mg/ml ascorbic acid.

Three weeks after operation, the rats were tested for rotationalbehavior in response to apomorphine hydrochloride (0.25 mg/kg, s.c.).Rats which consistently showed more than 5 turns/min after apomorphinewere selected and the compound of formula I was then administered. Therat was immediately placed in the rotometer, described by K. Voith andJ. R. Cummings, Can. J. Pharmacol., 54, 551 (1976), and the rotation wascontinuously recorded until drug effect subsided. By using this test,the compounds of formula I can be shown to be effective dopaminereceptor agonists.

A recently developed animal model, described by G. P. Smith and R. C.Young in "Advances in Neurology", Vol. 5, F. H. McDowell and A. Barbeau,Eds., Raven Press, New York, pp. 427-432 (1974), shows that rats exhibitalmost complete akinesia in an open field following the bilateralinjection of 6-OHDA into the anterolateral hypothalamus. Thetroponylpiperazines of formula I are able to reverse this 6-OHDA-inducedhypokinesia and as a result, function as dopamine receptor agonists. Inthis test for dopamine receptor agonists, the compounds of formula Iexhibit a pharmacological response that is quantitatively comparable tothat of apomophine and bromocriptine.

Experiments were performed on male Sprague-Dawley rats housed inair-conditioned quarters. The room was lighted between 0700 and 1900 hrdaily and was maintained at a temperature of 24° C.±2° C.

The method of Smith and Young, cited above, was followed. Rats(approximately 280 g) were operated on under sodium pentobarbitalanesthesia. Using a Stoelting stereotaxic instrument, the tip of a 26gauge cannula was positioned in the anterolateral hypothalamus (7 mmanterior to the interaural line, 2 mm lateral to the midline and 8 mmbelow the dura) according to the De Groot brain atlas, noted above. Viaa polyethylene tubing (PE 20) the cannula was connected to a 10 μlsyringe which was mounted in a Starrett micrometer head drive, C. H.Stoelting Co., Chicago, Ill., U.S.A. All injections were bilateral. Eachinjection consisted of 4 μl of distilled water containing 6-OHDA (6.5 μgbase/μl) and ascorbic acid (0.4 μg/μl).

The animals had free access to Purina Laboratory Chow pellets and tapwater. However since anterolateral hypothalamic 6-OHDA injectionsproduce aphagia and adipsia, intragastric feeding was necessary in orderto prevent drastic weight loss. The rats received a daily gastricintubation of 2 g of the "modified rat tube feeding diet" (ICNPharmaceuticals, Inc., Clevaland, Ohio, U.S.A.) mixed with approximately2 ml tap water.

Ambulation in the open field was evaluated in an apparatus consisting ofa wooden box (69 cm×69 cm×42 cm) with an arborite floor. The floor wasdivided into 36 squares (11.5 cm×11.5 cm). The placement of all fourlimbs in one square was taken as one ambulation score.

In the present experiments all compounds were evaluated four days afterthe intracerebral injection of 6-OHDA. The rat was placed into thecenter of the open field and observed for a 2-min period. Only rats withalmost total akinesia were used. Apomorphine, bromocriptine or thecompounds of formula I were injected s.c. to groups of 4-12 rats.Subsequently, the number of squares were counted which the animalentered during several 2-min observation periods. Apomorphine wasevaluated at 5, 10, 15, 20 and 30 min; bromocriptine at 2, 3, 4, 5, 6and 7 hr; and the compounds of formula I at 15, 30, 45, 60, 90 and 120min after injection. Each animal was used only once. The results areexpressed as cumulative number of ambulation scores which are the sumsof the scores obtained during the 2-min observation periods.

The following substances were used; apomorphine hydrochloride (MacfarianSmith Ltd., Edinburgh, Scotland), bromocriptine (CB-154) (SandozPharmaceuticals, East Hanover, N.J., U.S.A.) and 6-OHDA hydrobromide(Aldrich Chemical Co., Inc., Milwaukee, Wis.; U.S.A.). The compoundswere dissolved in distilled water or suspended in distilled water with afew drops of polysorbate 80 (Tween 80; "Tween" is a registered trademark). If the compound was an oil, 0.4 ml of dimethyl sulfoxide wasadded. Solutions were prepared fresh on the day of the experiment. The6-OHDA solution was kept in ice throughout the injection procedure. Alldoses refer to the base.

Using the above described method, apomorphine at a dose of 0.5 mg/kgexhibited a score of 135±41 and bromocriptine at a dose of 10 mg/kgexhibited a score of 112±23. Similarly, the following representativecompounds of formula I are effective dopamine receptor agonists (theamount of the compound and its cumulative ambulation score are indicatedin the parentheses):4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetonitrile(described in Example 3, at a dose of 50 mg/kg exhibited a score of126±51), 2-[4-(2-ethoxyethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(described in Example 3, at a dose of 50 mg/kg exhibited a score of67±16),2-[4-[2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(described in Example 4, at a dose of 10 mg/kg exhibited a score of101±28),2-[4-[2-(3,4-dihydroxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(described in Example 5, at a dose of 25 mg/kg exhibited a score of98±57), 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetamide(described in Example 6, at a dose of 50 mg/kg exhibited a score of42±14),2-[4-[2-(acetyloxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(described in Example 7, at a dose of 50 mg/kg exhibited a score of232±54), and 2,2-dimethylpropanoic acid,2-[4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazinyl]ethyl ester(described in Example 8, at a dose of 50 mg/kg exhibited a score of137±29).

The above described test method for dopamine receptor agonists showsthat the compounds of formula I are active as dopamine receptoragonists. The compounds, thus, can be used clinically in the treatmentof hyperprolactinemia, galactorrhoea, amenorrhoea, impotence, diabetes,Parkinsonism, acromegaly, hypertension and other central nervous systemdisorders which respond to dopaminereceptor stimulation.

The compounds of formula I of this invention are used alone or incombination with pharmacologically acceptable carriers, the proportionof which is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard biologicalpractice. For example, they are administered orally in solid form i.e.capsule or tablet. They can also be administered orally in the form ofsuspensions or solutions or they may be injected parenterally. Forparenteral administration they can be used in the form of a sterilesolution containing other solutes, for example, enough saline or glucoseto make the solution isotonic.

The tablet compositions contain the active ingredient in admixture withnon-toxic pharmaceutical excipients known to be suitable in themanufacture of tablets. Suitable pharmaceutical excipients are, forexample, starch, milk sugar, certain types of clay and so forth. Thetablets can be uncoated or they can be coated by known techniques so asto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period.

The aqueous suspensions of the compounds of formula I contain the activeingredient in admixture with one or more non-toxic pharmaceuticalexcipients known to be suitable in the manufacutre of aqueoussuspensions. Suitable excipients are, for example, methylcellulose,sodium alginate, gum acacia, lecithin and so forth. The aqueoussuspensions can also contain one or more preservatives, one or morecoloring agents, one or more flavoring agents and one or more sweeteningagents.

Non-aqueous suspensions can be formulated by suspending the activeingredient in a vegetable oil, for example, arachis oil, olive oil,sesame oil, or coconut oil, or in a mineral oil, for example liquidparaffin, and the suspension may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. These compositions can alsocontain a sweetening agent, flavoring agent and antioxidant.

The dosage of the compounds of formula I as dopamine receptor agonistswill vary with the form of administration and the particular compoundchosen. Furthermore, it will vary with the particular host as well asthe age, weight and condition of the host under treatment as well aswith the nature and extent of the symptoms. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under circumstances is reached. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects. For example, theeffective dopamine receptor stimulating amount of the compounds for i.p.administration usually ranges from about 0.1 mg to about 250 mg perkilogram body weight per day in single or divided doses although asaforementioned variations will occur. However a dosage level that is inthe range of from about 1.0 to about 100 mg per kilogram body weight perday in single or divided doses is employed most desirably for i.p.administration in order to achieve effective results. For oraladministration, effective amounts can range from about 1.0 to about 250mg per kilogram body weight per day in single or divided dosespreferably about 5.0 to 100 mg per kilogram body weight per day.

The compound of formula I, or a therapeutically acceptable salt thereof,also can be used to produce beneficial effects in the treatment ofParkinsonism, hyperprolactinemia and related disorders when combinedwith a therapeutically effective amount of an agent commonly used in thetreatment of Parkinsonism, hyperprolactinemia and related disorders.Such agents include, for example, apomorphine and its derivatives,piribedil and its derivatives, dopaminergic ergot derivatives,especially bromocriptine and iergotrile,2-amino-6,7-dihydroxy-(1,2,3,4)-tetrahydronaphthalene (ADTN),levodihydroxyphenylalanine (levodopa), combination of levodopa withcarbidopa, L-prolyl-L-leucylglycinamide (MIF) and its derivatives,especially L-prolyl-N-methyl-D-leucylglycinamide (pareptide), biperiden,cycrimine hydrochloride, procyclidine, trihexyphenidyl hydrochloride,benztropine mesylate, chlorphenoxamine hydrochloride, diphenhydraminehydrochloride, orphenadrine hydrochloride, ethopropazine hydrochlorideand the enzymes, monoamine oxidase B and catechol-O-methyl transferase.A combination of the foregoing agents can be substituted for a singleagent. Suitable methods of administration, compositions and dosages ofthe agents are well known in the art; for instance, "Physican DeskReference", 32 ed., Medical Economics Co., Oradell, N.J., U.S.A., 1978.When used in combination, the compound of formula I, or itstherapeutically acceptable salt, is administered as describedpreviously.

PROCESS

Reaction scheme 1 illustrates methods for preparing a number of thecompounds of formula I. ##STR3##

The 2-alkoxy-tropones, of formula II in which R³ is lower alkyl,suitable as starting materials are described in a number of reports; forexample, see the review on tropone derivatives, their preparation andtheir interconversions by F. Pietra, Chem. Rev., 73, 293 (1973). Thus,the 2-alkoxy-tropones are either known or they can be prepared byconventional means.

Also, the piperazine and piperazine derivatives of formulae III and IVare either known, commercially available or can be prepared byconventional means. For example, one useful method of preparing acompound of formula III, the appropriate nitrogen of the piperazine offormula IV wherein R¹ is as defined herein is first protected with anamino protecting group, for instance, benzyl, formyl,tert-butoxycarbonyl and the like. The desired Alk-R² group is thenintroduced onto the other nitrogen of this protected piperazine, variousmethods of introducing this group are described hereinafter. Subsequentremoval of the protecting group, for example, hydrogenation in the caseof benzyl, gives the corresponding piperazine derivative of formula III.

With reference to reaction scheme 1, the 2-alkoxy-tropone of formula IIin which R³ is lower alkyl, preferably methyl or ethyl, is condensedwith the piperazine derivative of formula III in which Alk is a divalentalkyl having one to six carbon atoms; R¹ is hydrogen or lower alkylhaving one to three carbon atoms; and R² is lower alkoxy, cyano,aminocarbonyl, lower alkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- ortrisubstituted with lower alkyl, halo, lower alkoxy, hydroxy ortrifluoromethyl, or phenoxy mono-, di- or trisubstituted with loweralkyl, halo, lower alkoxy, acetylamino, hydroxy or trifluoromethyl toobtain the corresponding compound of formula I in which Alk, R¹ and R²are as defined herein. The condensation is readily effected by heating asolution of the compound of formula II with one to five, preferably 1.3to 2.0, molar equivalents of the piperazine of formula III in an inertorganic solvent, for example, a lower alkanol, benzene, chloroform,acetonitrile, toluene and the like, preferably methanol or ethanol, at50° to 100° C. for 10 to 60 hours and isolating the correspondingcompound of formula I.

By using the above condensation conditions, condensation of the compoundof formula II with about one-half molar equivalent an1-[amino(lower)alkyl]piperazine gives the corresponding compound offormula I in which R¹ is as defined herein and R² is1-oxo-2,4,6-cycloheptatrien-2-ylamino.

The above described condensation of the compounds of formula II andformula III is especially useful for preparing the compounds of formulaI in which R¹ is as defined herein and R² is phenyl or1-oxo-2,4,6-cycloheptatrien-2-ylamino.

Condensation of the compound of formula II and the piperazine of formulaIV, in the same manner as described above for the compounds of formulaeII and III, gives the corresponding compound of formula V in which R¹ isas defined herein. The compound of formula V is condensed in thepresence of a proton acceptor with a halide of formula X--Alk--R²wherein X is bromo, chloro or iodo; Alk is a divalent alkyl having oneto six carbon atoms; and R² is lower alkoxy, cyano, aminocarbonyl, loweralkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- ortrisubstituted with lower alkyl, halo, lower alkoxy, hydroxy ortrifluoromethyl, or phenoxy, mono-, di- or trisubstituted with loweralkyl, halo, lower alkoxy, acetylamino, hydroxy or trifluoromethyl toobtain the corresponding compound of formula I in which Alk, R¹ and R²are as defined herein. About one to ten, preferably 1.0 to 1. molarequivalents of the proton acceptor and about one to five, preferably 1.0to 1.5, molar equivalents of the halide of formula X--Alk--R² are used.For this condensation, suitable proton acceptors can be selected fromorganic and inorganic proton acceptors, for example triethylamine,pyridine, N-ethylmorpholine, sodium bicarbonate, sodium or potassiumcarbonate, sodium or potassium lower alkoxide and the like. Sodium orpotassium carbonate is the preferred proton acceptor. Usually thecondensation is conducted in an inert organic solvent, for example,benzene, toluene, dichloromethane, chloroform, lower alkanol,acetonitrile, dimethylformide, acetone and the like. Acetonitrile and/ormethanol is the preferred solvent for the condensation. To achieve thecondensation, the reaction mixture is maintained at 20° to 85° C. forthree hours to three days and the compound of formula I is isolated.

Another useful condensation involves the reaction of the compound offormula V in which R¹ is as defined herein with about one molarequivalent of a tosylate of formula TsO--Alk--R² wherein Alk is asdefined herein R² is phenyl, phenoxy, phenyl mono-, di- ortrisubstituted with lower alkyl, halo, lower alkoxy or trifluoromethyl,or phenoxy mono-, di- or trisubstituted with lower alkyl, halo, loweralkoxy, acetylamino or trifluoromethyl to obtain the correspondingcompound of formula I in which Alk and R¹ are as defined herein and R²is as defined immediately above. This condensation requires the presenceof about two molar equivalents of a proton acceptor, preferably sodiumor potassium carbonate. An especially useful solvent for thiscondensation is acetone. The reaction mixture is maintained at about 50°to 60° C. for about 15 to 40 hours to obtain the corresponding compoundof formula I.

Treatment of the above described compound of formula I in which Alk andR¹ are as defined herein and R² is phenyl mono-, di- or trisubstitutedwith lower alkoxy with about four to ten molar equivalents of borontribromide in an inert organic solvent, preferably dichloromethane, at10° to 30° C. for about two to ten hours gives the correspondingcompound of formula I in which Alk and R¹ are as defined herein and R²is phenyl mono-, di- or trisubstituted with hydroxy.

The reaction of the above described compound of formula I in which Alkand R¹ are as described herein and R² is cyano with five to twenty molarequivalents of concentrated sulfuric acid at 10° to 30° C. for about twoto five days, followed by treatment with a mixture of ice andconcentrated ammonium hydroxide until the reaction is alkaline, givesthe corresponding compound of formula I in which Alk and R¹ are asdefined herein and R² is aminocarbonyl.

Intermediates of formula VI in which Alk and R¹ are as defined herein##STR4## and R⁴ is hydroxy or chloro are also useful for preparing somecompounds of formula I. A compound of formula VI in which Alk and R¹ areas defined herein and R⁴ is hydroxy is prepared by condensing a compoundof formula II in which R³ is as defined herein with a1-[hydroxy(lower)alkyl]-piperazine, in the same manner as describedabove for the condensation of the compounds of formulae II and III.

Acylation of the compound of formula VI in which Alk and R¹ are asdefined herein and R⁴ is hydroxy gives the corresponding compound offormula I in which Alk and R¹ are as defined herein and R² is1-oxo(lower)alkoxy. The acylation is achieved by reacting the lattercompound of formula VI with about an equimolar amount of a loweralkanoyl bromide or chloride and an organic proton acceptor, preferablytriethylamine or pyridine, in an inert organic solvent, preferablybenzene or dichloromethane, at 0° to 20° C. for one to three days, orwith an excess of a lower alkanoic anhydride in the presence of anorganic proton acceptor. When this acylation involves acetylation, apreferred method of acetylation is the reaction of the compound offormula VI with about 5 to 20 molar equivalents each of acetic anhydrideand pyridine at 20° to 50° C. for 10 to 30 hours to obtain thecorresponding compound of formula I in which Alk and R¹ are as definedherein and R² is acetyloxy.

Reaction of the compound of formula VI in which Alk and R¹ are asdefined herein and R⁴ is hydroxy with about two to three molarequivalents of thionyl chloride in an inert organic solvent, preferablychloroform, at about 10° to 30° C. for about 10 to 40 hours gives thecorresponding intermediate of formula VI in which Alk and R¹ are asdefined herein and R⁴ is chloro.

Reaction of the compound of formula VI in which Alk and R¹ are asdefined herein and R⁴ is chloro with about an equimolar amount ofthiourea in a solution of ethanol at about 70° to 80° C. for about oneto five hours gives the corresponding intermediate having an[(aminoiminomethyl)amino]thio group. Acetylation of this intermediatewith an excess of acetic anhydride, about 50 to 20 molar equivalents, atabout 40° to 80° C. for about 30 minutes to five hours gives thecorresponding compound of formula I in which Alk and R¹ are as definedherein and R² is acetylthio.

The following examples illustrate further this invention.

EXAMPLE 1 2-[4-(Phenylmethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂, R¹ =H and R² =phenyl)

A mixture of 1-(phenylmethyl)-piperazine (3.2 g) and2-methoxy-2,4,6-cycloheptatrien-1-one (1.6 g) in methanol (6 ml) wasrefluxed for 10 hr and evaporated. The residue was dissolved in amixture of chloroform and water. The organic phase was separated, driedand evaporated. The residue was chromatographed on silica gel (200 g)using methanol-chloroform (5:95). The eluates were evaporated to givethe title compound (2.7 g): mp 78°-80° C.; ir(CHCl₃) 2400, 1705, 1620,1350 and 1570 cm⁻¹ ; uv max(MeOH) 343 (ε=9440) and 250 nm (ε=14975);nmr(CDCl₃) δ2.9 (s, 3H), 3.5 (m, 8H), 6.27 (s, 2H), 7.0 (m, 5H) and 14.5(broad, 2H); and Anal. Calcd for C₁₈ H₂₀ N₂ O₂ : C, 77.11% H, 7.19% N,9.99% and Found: C, 77.08% H, 7.17% N, 9.74%.

In the same manner, but replacing 1-(phenylmethyl)-piperazine with anequivalent amount ofN-(2-oxo-2,4,6-cycloheptatrien-1-yl)-1-piperazinylethanamine, thefollowing compound of formula I wasobtained:N,4-bis-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanamine(I: R¹ =H, Alk=CH₂ CH₂ and R² =1-oxo-2,4,6-cycloheptatrien-2-ylamino):mp 130°-132° C. (crystallized from ethyl acetate); ir(CHCl₃) 3300 and1555 cm⁻¹ ; uv max(MeOH) 340 (ε=22740) and 248 nm (ε=40,285); nmr(CDCl₃)δ2.8 (m, 6H), 3.4 (m, 6H), 6.9 (m, 10H) and 7.6 (broad, 1H); and Anal.Calcd for C₂₀ H₂₃ N₃ O₂ : C, 71.19% H, 6.87% N, 12.45% and Found: C,71.60% H, 7.09% N, 12.40%.

EXAMPLE 2 2-(1-Piperazinyl)-2,4,6-cycloheptatrien-1-one (V: R¹ =H)

A solution of 2-methoxy-2,4,6-cycloheptatrien-1-one (136 g) andpiperazine (136 g) in methanol (250 ml) was refluxed for 4 hr and thereaction vessel was placed in an ice bath. Water (150 ml), then aceticacid was slowly added until the solution was acidic. The mixture wasfiltered and the filtrate was evaporated and chromatographed on silicagel using chloroform-acetone (1:1) and then with aceticacid-methanol(1:4). The eluates from the latter solvent were evaporatedto give an oil of the acetate salt (153 g) of the title compound.

Alternatively, the reaction solution was cooled to inducecrystallization of the dimer and filtered. The filtrate was diluted withacetone to 1000 ml and a solution of methane sulfonic acid (106 g) inacetone (250 ml) was added to the filtrate in an ice bath. Theprecipitate was collected and washed with acetone and diethyl ether togive 146 g of the methane sulfonate salt of the title compound: mp174°-176° C.; ir(mull) 2900, 1563 and 1180 cm⁻¹ ; uv max(MeOH) 343(ε=8910), 252 (ε=13110) and 223 nm(ε=11250); nmr(DMSO-d₆)δ2.35 (s, 3H),3.35 (m, 8H), 6.95 (m, 5H) and 8.8 (broad, 2H); and Anal. Calcd for C₁₁H₁₄ N₂ O.CH₃ SO₃ H: C, 50.32% H, 6.33% N, 9.80% and Found: C, 50.06% H,6.39% N, 9.44%.

EXAMPLE 3 4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetonitrile(I: Alk=CH₂, R¹ =H and R² =cyano)

A mixture of 2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one acetate (10.0g, described in Example 2), chloroacetonitrile (13.2 g) and potassiumcarbonate (14.5 g) in acetonitrile (110 ml) was stirred at roomtemperature for 16 hr, and filtered. The filtrate was evaporated. Theresidue was chromatographed on silica gel (300 g) using ethylacetate-acetone (4:1) give 1.9 g of the title compound, which was thencrystallized from acetone-diethyl ether: mp 133°-135° C.; ir(CHCl₃) 2230and 1565 cm⁻¹ ; uv max(MeOH) 350 (ε=9810), 254 (ε=14575) and 222nm(ε=11960); nmr(CDCl₃) δ2.75 (t, 4H), 3.4 (t, 4H), 3.55 (s, 2H) and 7.0(m, 5H); and Anal. Calcd for C₁₃ H₁₅ N₃ O: C, 68.4% H, 6.56% N, 18.38%and Found: C, 68.15% H, 6.68% N, 18.25%.

In the same manner but replacing chloroacetonitrile with an equivalentamount of ethyl bromoacetate, 2-phenoxyethyl bromide, 2-ethoxyethylbromide, 2-(2-chloroethoxy)-ethanol, phenethyl bromide,2-[4-(1,1-dimethylethyl)phenoxy]ethyl bromide, 2-(4-chlorophenoxy)ethylbromide, 2-[4-(acetylamino)phenoxy]ethyl bromide, 2-(3-indolyl)ethylbromide, 2-(1H-imidazol-4-yl)ethyl bromide or1-(p-toluenesulfonyl)-2-(4-fluorophenyl)ethane, the following compoundsof formula I were obtained respectively:4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine acetic acid, ethylester (Z)-2-butenedioate (I: Alk=CH₂, R¹ =H and R² =ethoxycarbonyl): mp106°-116° C. (crystallized from acetone-diethyl ether); ir(mull) 2340,1738, 1695 and 1553 cm⁻¹ ; uv max(MeOH) 344 (ε=7630) and 251nm(ε=12080); nmr(DMSO-d₆)δ1.25 (t, 3H), 3.0 (m, 4H), 3.4 (m, 4H), 3.7(s, 2H), 4.15 (q, 2 H), 6.15 (s, 2h) and 6.9 (m, 5H); and Anal. Calcdfor C₁₅ H₂₀ N₂ O₃.C₄ H₄ -O₄ 1/2H₂ O: C, 56.85% H, 6.28% N, 6.98% andFound: C, 56.52% H, 6.27% N, 6.74%;2-[4-(2-phenoxyethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (I:Alk=CH₂ CH₂, R¹ =H and R² =phenoxy): mp 94°-95° C. (crystallized fromethyl acetate-diethyl ether); ir(CHCl₃) 1565 cm⁻¹ ; uv max(MeOH) 351(ε=9840), 256 (ε=15580) and 219 nm(ε=21075); nmr (CDCl₃) δ2.75 (m, 6H),3.35 (m, 4H), 4.10 (t, 2H) and 7.0 (m, 9H); and Anal. Calcd for C₁₉ H₂₂N₂ O₂ : C, 73.52% H, 7.08% N, 9.02% and Found: C, 73.43% H, 7.16% N,8.97%; 2-[4-(2-ethoxyethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =ethoxy); mp 137°-138° C. (crystallizedfrom acetone-diethyl ether); ir(CHCl₃) 2450, 1900 and 1705 cm⁻¹ ; uvmax(meOH) 344 (ε=9470) and 251 nm(ε=14940); nmr(CDCl₃) δ1.2 (t, 3H),3.55 (m, 14H), 6.2 (s, 2H), 6.9 (m, 5H) and 13.3 (broad, 2H); and Anal.Calcd for C₁₅ H₂₂ N₂ O₂.C₄ H₄ O₄ : C, 60.30% H, 6.87% N, 7.40% andFound: C, 60.27% H, 6.89% N, 7.17%;2-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =2-hydroxyethoxy): ir(CHCl₃) 3660, 3400,1555 and 1612 cm⁻¹ ; uv max(MeOH) 351 (ε=8825), 255 (ε=12810) and 222nm(ε=10330); and nmr(CDCl₃) δ2.65 (m, 6H), 3.34 (t, 4H), 3.60 (m, 6H)and 6.60-6.95 (m, 5H);2-[4-(2-phenylethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (I:Alk=CH₂ CH₂, R¹ =H and R² =phenyl): ir(CHCL₃) 1365 cm⁻¹ ; uv max(MeOH)255 nm(ε=12290) and nmr(CDCl₃)δ2.75 (m, 8H), 3.35 (m, 4H) and 7.0 (m,10H);2-[4-[2-[4-(1,1-dimethylethyl)phenoxy]ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =4-(1,1-dimethylethyl)phenoxy): ir(CHCl₃)1565 cm⁻¹ ; uv max(MeOH) 351 (ε=9830), 256 (ε=15290) and 223nm(ε=22515); nmr(CDCl₃)δ1.30 (s, 9H), 2.80 (m, 6H), 3.40 (m, 4H), 4.15(t, 2H) and 7.00 (m, 9H); and Anal. Calcd for C₂₃ H₃₀ N₂ O₂ : C, 75.37%H, 8.25% N, 7.65% and Found: C, 75.07% H, 8.15% N, 7.67%;2-[4-[2-(4-chlorophenoxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =4-chlorophenoxy): mp 89°-91° C.(crystallized from ethyl acetate); ir(CHCl₃) 1565 cm⁻¹ ; uv max(MeOH)351 (ε= 9575), 255 (ε=14625) and 227 nm (ε=23650); nmr(CDCl₃)δ2.80 (m,6H), 3.40 (t, 4H), 4.10 (t, 2H) and 7.00 (m, 9H); and Anal. Calcd forC₁₉ H₂₁ ClN₂ O₂ : C, 66.17% H, 6.14% N, 8.12% and Found: C, 65.94% H,6.13% N, 8.09%;2-[4-[2-[4-(acetylamino)phenoxy]ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =4-(acetylamino)phenoxy): mp 141°-143° C.;ir(CHCl₃) 3430, 3300, 1680 and 1560 cm⁻¹ ; uv max (MeOH) 351 (ε=9990)and 252 nm(ε=30610); nmr(CDCl₃) δ2.10 (s, 3H), 2.80 (m, 6H), 3.40 (t,4H), 4.10 (t, 4H) and 7.00 (m, 9H); and Anal. Calcd for C₂₁ H₂₅ N₃ O₃ :C, 68.64% H, 6.86% N, 11.44% and Found: C, 68.48% H, 6.76% N, 11.31%;2-[4-[2-(3-indolyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrie-1-one (I:Alk=CH₂ CH₂, R¹ =H and R² =3-indolyl): mp 128°-129° C. (crystallizedfrom ethyl acetate-hexane); ir(mull) 3310 and 1555 cm⁻¹ ; uv max(MeOH)352 (ε=9700), 290 (ε=8680), 257 (ε=16960) and 222 nm(ε=46990);nmr(DMSO-d₆) δ2.60 (m, 8H), 3.25 (m, 4H), 7.00 (m, 10H) and 10.2 (s,1H); and Anal. Calcd for C₂₁ H₂₃ N₃ O: C, 75.65% H, 6.95% N, 12.60% andFound: C, 75.53% H, 7.11% N, 12.47%;2-[4-[2-(1H-imidazol-4-yl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =1H-imidazol-4-yl): mp 139°-141° C.(crystallized from acetone-diethyl ether); ir(mull) 2800 and 1560 cm⁻¹ ;uv max(MeOH) 350 (ε=9970) and 255 nm(ε=14915); nmr(CDCl₃) δ2.57 (m, 8H),3.40(m, 4H) and 7.00); and Anal. Calcd for C₁₆ H₂₀ N₄ O: C, 67.58% H,7.09% N, 19.71% and Found: C, 67.10% H, 7.09% N, 19.64%; and2-[4-[2-(4-fluorophenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-onehydrochloride (I: Alk=CH₂ CH₂, R¹ =H and R² =4-fluorophenyl): mp 208°-210° C.; ir(nujol) 2280 cm⁻¹ ; uv max(MeOH) 343 (ε=9700), 251 (ε=14315)and 222 nm (ε=11555); nmr(DMSO-d₆)δ3.4(m, 12H) and 7.1 (m, 9H); andAnal. Calcd for C₁₉ H₂₁ FN₂ O: C, 65.40% H, 6.35% N, 8.06% and Found: C,65.27% H, 6.37% N, 8.04%.

EXAMPLE 42-[4-[2-(3,4-Dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H and R² =3,4-dimethoxyphenyl)

To a solution of 3,4-dimethoxyphenethanol (4.4 g) in methylene chloride(15 ml) containing triethylamine (2.7 g or 3.7 ml), was added graduallya solution of tosyl chloride (5.07 g) in methylene chloride (15 ml). Themixture was stirred at room temperature overnight. The mixture wasdiluted with chloroform and washed with water. The organic layer wasseparated, dried and evaporated to yield a crude product (11.7 g). Theproduct was passed through a column of silica gel (250 g) and theeluates were evaporated to give 3,4-dimethoxyphenethyl tosylate (7.2 g):ir(CHCl₃) 1600 and 1500 cm⁻¹ ; and nmr(CDCl₃) δ2.4 (s, 3H), 2.85 (m,2H), 3.72 (s, 3H), 3.75 (s, 3H), 4.15 (t, 2H), 6.6 (m, 2H), 7.23 (m, 3H)and 7.64 (m, 2H).

A mixture of the latter compound (15.4 g),2-(1-piperazinyl)-2,4,6-cycloheptatrien-1-one acetate (10.4 g, describedin Example 2) and potassium carbonate (12.54 g) in acetone (105 ml) wasrefluxed for 24 hr and evaporated. A solution of the residue inchloroform was washed with water, dried and evaporated. The residue wastreated with a solution of hydrogen chloride in diethyl ether and theprecipitate was collected and crystallized from methanol to obtain thehydrochloride salt (8.53 g) of the title compound, mp 175°-178° C. Thelatter salt (3.2 g) was dissolved in water and 10% sodium hydroxide wasadded until the solution was alkaline. After extraction with chloroform,the extract was dried, evaporated and crystallized from diethylether-hexane to obtain the title compound (2.0 g): mp 83°-85° C.;ir(CHCl₃) 1565, 1200 and 1145 cm⁻¹ ; uv max(MeOH) 350 (ε=9860), 256(ε=15130) and 227 nm(ε=19500); nmr(CDCl₃)δ2.7 (m, 2H), 3.4 (m, 4H), 3.85(s, 6H) and 6.8 (m, 8H); and Anal. Calcd for C₂₁ H₂₆ N₂ O₃ : C, 71.16%H, 7.39% N, 7.91% and Found: C, 71.31% H, 7.62% N, 7.78%.

EXAMPLE 52-[4-[2-(3,4-Dihydroxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk=CH₂ CH₂, R¹ =H, and R² =3,4-dihydroxyphenyl)

A solution of2-[4-[2-(3,4-dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(1.10 g, described in Example 4) in methylene chloride (5 ml) was cooledto -65° C. in dry ice bath. A solution of boron tribromide (3.36 g) inmethylene chloride (5 ml) was added dropwise to the solution of thecompound. After the addition, the temperature was allowed to rise toroom temperature. After 4 hr, the mixture was cooled in an ice bath andmethanol (20 ml) was added dropwise. The resulting mixture was slowlybrought to reflux and the solid was allowed to dissolve. The solutionwas then concentrated to the point at which crystals start to separate.Some diethyl ether was added, the mixture was cooled overnight, andfiltered to give crude product (1.4 g). Recrystallization form methanolgave the hydrobromide salt (0.5 g) of the title compound: mp 256°-258°C.; ir(nujol) 3490, 2540 and 1522 cm⁻¹ ; uv max(MeOH) 342 (ε=7820), 250(ε=10720) and 222 nm(ε=11535); nmr(DMSO-d₆)δ3.25 (m, 12H), 6.8 (m, 7H)and 8.7 (broad, 2H); and Anal. Calcd for C₁₉ H₂₂ N₂ O₃.HBr: C, 56.02% H,5.69% N, 6.88% and Found: C, 55.91% H, 5.74% N, 6.86%.

EXAMPLE 6 4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetamide(I: Alk=CH₂, R¹ =H and R² =aminocarbonyl)

A solution of4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetonitrile (3.0 g;described in Example 3) in conc. sulfuric acid (30 ml) was allowed tostay at room temperature for 3 days. The reaction mixture was pouredover ice and conc. ammonium hydroxide slowly while stirring, thenextracted with chloroform. Evaporation of the solvent left 2.7 g crudeproduct, which was recrystallized from methanol to yield 2.2 g of thetitle compound: mp 169°-171° C.; ir(CHCl₃) 3500, 3430, 3370, 1685 and1563 cm⁻¹ ; uv max(MeOH) 351 (ε=9920), 254 (ε=14810) and 221nm(ε=12090); nmr(CDCl₃)δ2.75 (t, 4H), 3.09 (s, 2H), 3.35 (t, 4H), 6.00(2H) and 6.8 (m, 5H); and Anal. Calcd for C₁₃ H₁₇ N₃ O₂ : C, 63.14% H,6.93% N, 16.99% and Found: C, 63.24% H, 7.00% N, 16.99%.

EXAMPLE 72-[4-[2-(Acetyloxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one (I:Alk=CH₂ CH₂, R¹ =H and R² =acetyloxy)

A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g) and2-methoxy-2,4,6-cycloheptatrien-1-one (10.9 g) in methanol (50 ml) wasrefluxed for 24 hr and evaporated. The residue was chromatographed onsilica gel (100 g) using methanol-ethyl acetate (1:4). The eluates wereevaporated and crystallized from ethyl acetate-hexane to give4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (9.2 g): mp85°-86° C.; ir(CHCl₃) 3440, 1616 and 1555 cm⁻¹ ; nmr(CDCl₃) δ2.55 (t,2H), 2.63 (m, 4H), 3.30 (m, 4H), 3.60 (t, 2H) and 6.40-7.65 (m, 5H); andAnal. Calcd for C₁₃ H₁₈ N₂ O₂ : C, 66.64% H, 7.74% N, 11.96% and Found:C, 66.12% H, 7.83% N, 11.99%.

To a solution of the latter compound (0.70 g) in pyridine (5 ml), aceticanhydride (15 ml) was added and the reaction mixture was allowed to stayat room temperature for 16 hr and evaporated. The residue waschromatographed on 50 g of silica gel with methanol-ethyl acetate(20:80) to yield 950 mg of still impure product. It wasrechromatographed on 100 g silica gel with methanol-ethyl acetate (5:95)to obtain 780 mg of the pure title compound as an oil: ir(CHCl₃) 1730and 1560 cm⁻¹ ; uv max(MeOH) 351 (ε=9445) and 255 nm(ε=14240); andnmr(CDCl₃)δ2.08 (s, 3H), 2.7 (t, 6H), 3.35 (t, 4H), 4.2 (t, 2H) and 6.9(m, 5H).

EXAMPLE 8 2,2-Dimethylpropanoic Acid,2-[4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazinyl]ethyl Ester (I:Alk=CH₂ CH₂, R¹ =H, and R² =2,2-dimethyl-1-oxopropoxy)

To a solution of4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (7.04 g,described in Example 7) in methylene chloride (100 ml), triethylamine(4.3 g) was added followed by the dropwise addition of2,2-dimethylpropanoyl chloride. The resulting solution was allowed tostay at room temperature for 3 days, then washed with water, dried oversodium sulfate and evaporated. The residue was chromatographed twice on250 g of silica gel with ethyl acetate to yield 3.5 g of the titlecompound. The title compound (3.0 g) was dissolved in acetone (15 ml)and a solution of maleic acid (1.16 g) in acetone (15 ml) was added.Diethyl ether (100 ml) was added to give the (Z)-2-butenedioate salt(2.5 g) of the title compound; mp 101°-102° C.; ir(mull) 2350, 1723,1700 and 1545 cm⁻¹ ; uv max(MeOH) 343 (ε=8040) and 251 nm(ε=12645);nmr(DMSO-d₆ ) δ1.2 (m, 9H), 3.3 (m, 10H), 4.3 (m, 2H), 6.1 (s, 2H) and6.95 (m, 5H); and Anal. Calcd for C₁₈ H₂₆ N₂ O₃.C₄ H₄ O₄ : C, 60.82% H,6.96% N, 6.45% and Found: C, 60.74% H, 7.01% N, 6.16%.

EXAMPLE 92-[4-[2-(Acetylthio)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one(I: Alk= CH₂ CH₂, R¹ =H and R² =acetylthio)

A mixture of 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol(10.0 g, described in Example 7), potassium carbonate (26 g) andchloroform (150 ml) was stirred and cooled in an ice-bath. Thionylchloride (11.7 g) was added dropwise over a period of 30 min and allowedto react with stirring at room temperature for 16 hr. Water (50 ml) wasadded and extracted with chloroform. After drying over magnesiumsulfate, the extract was evaporated and the residue (11.0 g) waschromatographed on 500 g silica gel with ethyl acetate to yield 6.2 g of2-[4-(2-chloroethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one mp71°-73° C.; ir(CHCl₃) 1560 cm⁻¹ ; uv max(MeOH) 352 (ε=9730) and 255nm(ε=14300); nmr(CDCl₃) δ2.75 (m, 6H), 3.5 (m, 6H) and 7.0 (m, 5H) andAnal. Calcd for C₁₃ H₁₇ --ClN₂ O: C, 61.77% H, 6.78% N, 11.08% andFound: C, 61.60% H, 6.79% N, 10.98%.

A mixture of the latter compound (2.53 g), thiourea (800 mg) and ethanol(25 ml) was refluxed for 2 hr and evaporated. The residue was dissolvedin water and washed with chloroform. The aqueous layer was freeze-driedto yield 3.06 of the hydrochloride salt of2-[4-[2-[[(aminoiminomethyl)amino]thio]ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one.A part of this salt (1.5 g) was stirred at 50° C. with 25 ml aceticanhydride for 45 min and cooled to room temperature. Methanol (10 ml)was added and the solution was evaporated to dryness in vacuo, to obtain2.87 g of crude product. It was dissolved in ethyl acetate, washed firstwith 10% sodium hydroxide, then, with water, dried over sodium sulfateand evaporated to give a residue (1.2 g). This residue waschromatographed on silica gel using ethyl acetate to give the titlecompound (0.39 g): mp 75°-77° C.; ir(CHCl₃) 1680, 1610 and 1560 cm⁻¹ ;uv max(MeOH) 351 (ε=8960), 254 (ε=13930) and 225 nm(ε=14100); nmr(CDCl₃)δ2.67 (m, 6H), 3.03 (t, 2H), 3.34 (t, 4H) and 6.60-7.20 (m, 5H); andAnal. Calcd for C₁₅ H₂₀ N₂ O₂ S: C, 61.63% H, 6.90% N, 9.58% and Found:C, 61.68%H, 6.95% N, 9.46%.

We claim:
 1. A compound of the formula ##STR5## in which Alk is adivalent alkyl having one to six carbon atoms; R¹ is hydrogen or loweralkyl having one to three carbon atoms; and R² is lower alkoxy, cyano,aminocarbonyl, lower alkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di ortrisubstituted with lower alkyl, halo, lower alkoxy, hydroxy ortrifluoromethyl, or phenoxy mono-, di- or trisubstituted with loweralkyl, halo, lower alkoxy, acetylamino, hydroxy or trifluoromethyl; or atherapeutically acceptable acid addition salt thereof.
 2. A compound ofclaim 1 in which Alk is a divalent alkyl having one to six carbon atoms;R¹ is hydrogen; and R² is lower alkoxy, cyano, aminocarbonyl, loweralkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- ortrisubstituted with lower alkoxy or hydroxy, or phenyl mono-, di- ortrisubstituted with lower alkyl, halo or acetylamino; or atherapeutically acceptable acid addition salt thereof.
 3. A compound ofclaim 1 in which Alk is a divalent alkyl having one to three carbonatoms; R¹ is hydrogen; and R² is lower alkoxy, cyano, aminocarbonyl,lower alkoxycarbonyl cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono- ordisubstituted with lower alkoxy or hydroxy, or phenoxy monosubstitutedwith lower alkyl, halo or acetylamino; or a therapeutically acceptableacid addition salt thereof.
 4. A compound of claim 1 in which Alk is adivalent alkyl having one or two carbon atoms; R¹ is hydrogen; and R² islower alkoxy, cyano, 1-oxo(lower)alkoxy, or phenyl mono- ordisubstituted with lower alkoxy or hydroxy; or a therapeuticallytherapeutically acid addition salt thereof. 5.2-[4-(Phenylmethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂, R¹ is hydrogen and R² is phenyl.6. N,4-Bis-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanamine, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is1-oxo-2,4,6-cycloheptatrien-2-ylamino. 7.4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine acetic acid, ethylester, a compund of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen andR² is ethoxycarbonyl. 8.4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetonitrile, acompound of claim 1 wherein Alk is CH₂, R¹ is hydrogen and R² is cyano.9. 2-[4-(2-(Phenoxyethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂ Ch₂, R¹ is hydrogen and R² isphenoxy. 10.2-[4-(2-Ethoxyethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² isethoxy. 11.2-[4-[2-(2-Hydroxyethoxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is2-hydroxyethoxy. 12.2-[4-(2-phenylethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² isphenyl. 13.2-[4-[2-(3,4-Dimethoxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is3,4-dimethoxyphenyl. 14.2-[4-[2-(3,4-Dihydroxyphenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is3,4-dihydroxyphenyl. 15.4-(2-Oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-acetamide, a compoundof claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² isaminocarbonyl. 16.2-[4-[2-(Acetyloxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² isacetyloxy.
 17. 2,2-Dimethylpropanoic acid,2-[4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazinyl]ethyl ester, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is2,2-dimethyl-1-oxopropoxy. 18.2-[4-[2-[4-(1,1-Dimethylethyl)phenoxy]ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is4-(1,1-dimethylethyl)phenoxy. 19.2-[4-[2-(4-Chlorophenoxy)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is4-chlorophenoxy. 20.2-[4-[2-[4-(Acetylamino)phenoxy]ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is4-acetylamino)phenoxy). 21.2-[4-[2-(3-Indolyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is3-indolyl. 22.2-[4-[2-(1H-Imidazol-4-yl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is1H-imidazol-4-yl. 23.2-[4-[2-(Acetylthio)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one, acompound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² isacetylthio. 24.2-[4-[2-(4-Fluorophenyl)ethyl]-1-piperazinyl]-2,4,6-cycloheptatrien-1-one,a compound of claim 1 wherein Alk is CH₂ CH₂, R¹ is hydrogen and R² is4-fluorophenyl.
 25. A pharmaceutical composition, for stimulatingdopamine receptors in a mammal in need thereof, which comprises aneffective dopamine receptor stimulating amount of a compound of theformula ##STR6## in which Alk is a divalent alkyl having one to sixcarbon atoms; R¹ is hydrogen or lower alkyl having one to three carbonatoms; and R² is lower alkoxy, cyano, aminocarbonyl, loweralkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- ortrisubstituted with lower alkyl, halo, lower alkoxy, hydroxy ortrifluoromethyl, or phenyl mono-, di- or trisubstituted with loweralkyl, halo, lower alkoxy, acetylamino, hydroxy or trifluoromethyl; or atherapeutically acceptable acid addition salt thereof, and apharmaceutically acceptable carrier therefor.
 26. A method ofstimulating dopamine receptors in a mammal in need thereof, whichcomprises administering to said mammal and effective dopamine receptorstimulating amount of a composition of claim
 25. 27. A method ofstimulating dopamine receptors in a mammal in need thereof, whichcomprises administering to said mammal an effective dopamine receptorstimulating amount of a composition of claim 25, in combination with aneffective amount of an agent selected from bromocriptine, lergotrile,levodopa, combination of levodopa and carbidopa,L-prolyl-L-leucylglycinamide and L-prolyl-N-methyl-D-leucylglycinamide.28. The method of claim 27 wherein the composition of claim 25, and saidagent are administered sequentially or simultaneously.
 29. Apharmaceutical composition for stimulating dopamine receptors in amammal in need thereof comprising an effective dopamine receptorstimulating amount of a compound of the formula ##STR7## in which Alk isa divalent alkyl having one to six carbon atoms; R¹ is hydrogen or loweralkyl having one to three carbon atoms; and R² is lower alkoxy, cyano,aminocarbonyl, lower alkoxycarbonyl, cyclo(lower)alkyl, phenyl, phenoxy,hydroxy(lower)alkoxy, 3-indolyl, 1-oxo-2,4,6-cycloheptatrien-2-yl-amino,1H-imidazol-4-yl, 1-oxo(lower)alkoxy, acetylthio, phenyl mono-, di- ortrisubstituted with lower alkyl, halo, lower alkoxy, hydroxy ortrifluoromethyl, or phenoxy mono-, di- or trisubstituted with loweralkyl, halo, lower alkoxy, acetylamino, hydroxy or trifluoromethyl; or atherapeutically acceptable acid addition salt thereof, and an agentselected from bromocriptine, lergotrile, levodopa, combination oflevodopa and carbidopa, L-propyl-L-leucylglycinamide andL-propyl-N-methyl-D-leucylglycinamide.